Kava — interactions

Additive hepatotoxicity — provides, moderate

Two or more agents with documented liver injury signals taken together. Not a pharmacokinetic interaction; the additivity is at the organ.

Sources: Gurley BJ 2005 · more on Additive hepatotoxicity

GABA-A positive modulation — agonist, moderate

Increases the effect of GABA at the GABA-A receptor without being GABA. The shared mechanism of alcohol, the benzodiazepines, the Z-drugs and the kavalactones. Additivity across agents on this axis is the mechanism behind sedation deepening into respiratory depression.

Kavain and the other major kavalactones potentiate GABA-A currents by a mechanism distinct from the benzodiazepine site. This is the axis that makes combination with alcohol, benzodiazepines, Z-drugs or opioids the practical hazard rather than any of the exotic mechanisms below.

Sources: Chua HC 2016, Sarris J 2009 · more on GABA-A positive modulation

Additive CNS depression — agonist, moderate

Sedation, impaired coordination, and at sufficient combined load impaired airway protection and breathing. The most common serious harm in this whole corpus and the least exotic. It does not need a metabolic interaction to happen: the agents simply add.

Sources: Chua HC 2016 · more on Additive CNS depression

FAAH inhibition — inhibits, weak

Slows fatty acid amide hydrolase, the enzyme that breaks down anandamide and the related fatty-acid amides. Raises anandamide tone rather than adding an outside agonist. Additive with anything else acting on the same system, and the clinical FAAH-inhibitor programmes are a reminder that an enzyme inhibitor is not inherently mild.

Reported from in-vitro enzyme assays. A micromolar IC50 in a dish does not establish that a dietary, tea or capsule dose reaches that concentration at the enzyme in a person, and for most of these compounds no human pharmacokinetic study exists. Treated here as a mechanism worth knowing about, not as an established clinical effect.

Sources: Ligresti A 2012 · more on FAAH inhibition

MAGL inhibition — inhibits, weak

Slows monoacylglycerol lipase, which performs the large majority of 2-AG hydrolysis in brain. Raises 2-AG and simultaneously diverts it away from the arachidonic-acid pool. Sustained complete blockade produces CB1 desensitisation in animals, so more inhibition is not simply more effect.

Reported from in-vitro enzyme assays. A micromolar IC50 in a dish does not establish that a dietary, tea or capsule dose reaches that concentration at the enzyme in a person, and for most of these compounds no human pharmacokinetic study exists. Treated here as a mechanism worth knowing about, not as an established clinical effect.

Sources: Ligresti A 2012 · more on MAGL inhibition

CB1 agonism (partial) — agonist, weak

Activates the CB1 receptor as a partial agonist, as the plant cannabinoids do. Partial agonism has a ceiling: beyond a point more drug does not produce more receptor activation. That ceiling is the reason cannabis does not depress respiration to the point of death.

Yangonin binds CB1 with a reported Ki near 720 nM — the same order as the endocannabinoid 2-AG at roughly 472 nM. Binding affinity is not efficacy, and what yangonin does at the receptor once bound is less well characterised than the binding itself.

Sources: Ligresti A 2012 · more on CB1 agonism (partial)

MAO-B inhibition — inhibits, weak

Blocks monoamine oxidase B, which preferentially handles dopamine and phenylethylamine. At low, B-selective doses the tyramine hazard is much smaller; selectivity is lost as dose rises.

All six major kavalactones inhibit MAO-B reversibly in vitro. B-selective and reversible inhibition carries a much smaller dietary-tyramine hazard than a non-selective irreversible MAOI, which is why this is scored weak rather than dropped.

Sources: Mathews JM 2002 · more on MAO-B inhibition

CYP2C9 inhibition — inhibits, moderate

Slows the enzyme handling S-warfarin, phenytoin and NSAIDs. S-warfarin is the clinically dominant enantiomer; small shifts move the INR.

Methysticin and dihydromethysticin are the potent inhibitors in vitro, with CYP2C9 and CYP2C19 the most affected. Note the disagreement worth carrying: in the Gurley human probe study kava did NOT significantly move CYP3A4 or CYP2D6, while it did inhibit CYP2E1. In vitro potency and in vivo probe results point in different directions here and the honest reading keeps both.

Sources: Mathews JM 2002, Gurley BJ 2005 · more on CYP2C9 inhibition

CYP2C19 inhibition — inhibits, moderate

Slows the enzyme handling clopidogrel activation, PPIs and some benzodiazepines. For clopidogrel the effect is loss of antiplatelet activity, not accumulation.

Same in-vitro source as CYP2C9, same in-vivo caveat.

Sources: Mathews JM 2002 · more on CYP2C19 inhibition

CYP2E1 inhibition — inhibits, moderate

Slows the enzyme handling ethanol at higher concentrations and the bioactivation of paracetamol to NAPQI. Both directions matter: inhibition and induction change how much reactive metabolite the liver makes, which is why this enzyme is a hepatotoxicity axis rather than a plain clearance one.

The one CYP effect the Gurley human probe study did find. CYP2E1 is the paracetamol bioactivation pathway, which connects a CYP finding to the hepatotoxicity signal on the same substance.

Sources: Gurley BJ 2005 · more on CYP2E1 inhibition